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Enhancer Role of STAT5 in CD2 Activation of IFN- Gene Expression¹

Rivkah Gonsky^*, Richard L. Deem^*, Jay Bream, Howard A. Young and Stephan R. Targan^2,*

^* Inflammatory Bowel Disease Research Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048; Lymphocyte Cell Biology Section, Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases Intramural Research Program, National Institutes of Health, Bethesda, MD 20892; and Cellular and Molecular Immunology Section, Laboratory of Experimental Immunology, National Cancer Institute, Frederick, MD 21702

IFN- is an important immunoregulatory protein with tightly controlled expression in activated T and NK cells. Three potential STAT binding regions have been recognized within the IFN- promoter: 1) an IL-12-mediated STAT4 binding site at –236 bp; 2) a newly identified IL-2-induced STAT5 binding element at –3.6 kb; and 3) CD2-mediated STAT1 and STAT4 binding to an intronic element in mucosal T cells. However, functional activation of these sites remains unclear. In this study we demonstrate CD2-mediated activation of the newly characterized –3.6-kb IFN- STAT5 binding region. CD2 signaling of human PBMC results in activation of the –3.6-kb IFN- promoter, whereas mutation of the –3.6-kb STAT5 site attenuates promoter activity. Functional activation is accompanied by STAT5A but little STAT5B nucleoprotein binding to the IFN- STAT5 site, as determined by competition and supershift assays. STAT5 activation via CD2 occurs independent of IL-2. Western and FACS analysis shows increased phospho-STAT5 following CD2 signaling. AG490, a tyrosine kinase inhibitor affecting Jak proteins, inhibits CD2-mediated IFN- mRNA expression, secretion, and nucleoprotein binding to the IFN- STAT5 site in a dose-dependent fashion. This report is the first to describe CD2-mediated activation of STAT5 and supports STAT5 involvement in regulation of IFN- expression.

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